Infectious diseases, including virus-induced respiratory infections and resultant acute lung injury, pose a considerable challenge to afflicted individuals, to the development of effective treatment modalities and to public health initiatives at large and the effective control of viral infections will require a more detailed understanding o the immune mechanisms involved in the eradication of relevant pathogens. An essential component of most antiviral and many antibacterial immune responses is the generation of pathogen-specific CD8+T cell immunity. Following resolution of acute disease or successful vaccination regimens, specific CD8+ effector T cells (CD8+TE) are subject to a gradual differentiation process that culminates in the establishment of specific CD8+T cell memory. Upon re-infection with the same or related viral pathogens, virus-specific CD8+ memory T cels (CD8+TM), together with neutralizing antibodies, provide enhanced protection due to their capacity to curtail viral spread, minimize clinical disease and avert potential death of infected hosts. In an effort to define the molecular, phenotypic and functional properties of highly protective CD8+TM, we have made the unexpected discovery that the development of robust secondary CD8+T cell responses is contingent upon effective adenosine generation and signaling in a CD8+TM-intrinsic fashion. The notion that adenosine generation/signaling can potentiate virus-specific CD8+T cell responses constitutes a novel concept, challenges the prevailing consensus about adenosine as a primarily immunosuppressive agent, and suggests the possibility of novel therapeutic avenues for promotion of antiviral T cell immunity. Here, we have developed a research plan that will identify, interrogate and characterize the molecular components in the adenosine generation/signaling pathway that promote secondary reactivity of virus- specific CD8+TM, that will define the precise patho-physiological context for proinflammatory adenosine generation and signaling (Specific Aims 1 and 2), and that will harness relevant insights obtained in the process of these studies for the development of novel therapeutic approaches that aim to amplify protective CD8+T cell immunity in a model for influenza virus-induced acute lung injury (Specific Aim 3). The continued and considerable burden of virus-induced acute lung injury, especially among pediatric and geriatric populations, emphasizes the urgent need for novel treatment approaches. We believe that the combination of mechanistic, contextual and pre-clinical studies as proposed in the present application has the potential to provide a rational foundation for the development of such therapeutic strategies. PUBLIC HEALTH RELEVANCE: Protection against respiratory and other infections is critically dependent on pathogen-specific T cell immunity. Here, we have made the novel and surprising discovery that adenosine generation and signaling potentiates virus-specific T cell immunity. We have therefore developed a research plan that will identify, interrogate and characterize specific molecular components of the adenosine generation/signaling pathway involved in regulation of antiviral T cell responses, and will integrate our findings into a novel adjunctive therapy approach for the treatment of acute influenza infections.